Five Challenges Of Applying Lipid Nanoparticles As Delivery Tools For Therapeutic Agents
As effective as these delivery vehicles are, they come with their own set of difficulties.
Recently, lipid nanoparticles (LNPs) have emerged as a particularly effective non-viral delivery vehicle for therapeutic agents, most notably for their use in mRNA COVID-19 vaccines.
LNPs are non-viral synthetic nanoparticles that consist of lipids that can encapsulate different cargos, such as nucleotides, proteins, and peptides, among others. LNPs protect these therapeutic agents as they deliver them across cell membranes to their target organs or tissues.
In general, LNPs are efficient, safe, and stable. There are, however, some key challenges that need to be considered when using this promising delivery vehicle.
1. Delivery Efficiency
Ensuring that LNPs effectively deliver their payload to the target cells remains a significant challenge for a number of reasons.
After being administered systemically, LNPs must evade interception by the mononuclear phagocytic system and clearance by renal glomerular filtration. Then they must reach the target tissue and be internalized by target cells. In the case of LNPs that are the delivery vehicles for mRNA, LNPs must also escape endosomes to reach the cytoplasm, where translation occurs.
2. Extrahepatic Targeting Specificity
Following intravenous injection, 80-90% of LNPs intended for extrahepatic organs or tissue end up in the liver and are taken up by hepatocytes via LDL receptors. This leaves less than 5% of the administered dose to be delivered to the intended organs or tissues.
This accumulation of nanoparticles in the liver can be problematic because it both decreases therapeutic efficacy by reducing the availability of LNPs for other organs or tissues and because non-specific distribution may lead to off-target effects.
Recently, a lot of research is focused on targeting extrahepatic organs or tissues. Although precise targeting has proven difficult, some promising novel strategies have recently been discovered in the form of selective organ targeting (SORT) molecules.
3. Safety
The use of LNPs as a drug delivery vehicle is generally considered to be safe. Currently, four LNP drug products have been approved and nine more are in phase III clinical trials.
Therapies that use LNPs as their delivery vehicle do have the potential, however, to evoke an immune response. To decrease this possibility, patients who are treated with LNP-based drugs may receive additional medications beforehand. For example, patients are administered a combination of dexamethasone, acetaminophen, and antihistamines before being administered the LNP-based drug ONPATTRO (patisiran).
4. Stability
Maintaining the stability of an LNP formulation is crucial. Instability can lead to degradation of the genetic material and reduced effectiveness.
A number of factors affect the stability of LNP formulations, including the way a formulation is prepared for storage, such as through lyophilization, the form and state in which it is stored – as a liquid at above 0°C or as a solid at below 0°C – and, in the latter case, which cryoprotectants are used.
In order to further improve the stability of LNP formulations, more investigation needs to be done into the many factors that impact them during storage.
5. Cost
In the case of using LNPs as a mRNA delivery vehicle, the initial development cost are currently higher than for viral-vector based therapies, but the entire drug development process of LNP formulations can be made cost effective by strategically reusing components and/or platforms from previously approved formulations.
It is less likely that regulatory problems will arise in the preclinical or clinical phases if the drug product being tested contains components and/or a platform that are part of another drug that has already been approved. For example, the FDA and EMA both approved Moderna’s mRESVIA mRNA vaccine very quickly because it contains the same lipid components found in the previously approved Spikevax vaccine.
To summarize, LNPs face significant challenges, including stability, targeted delivery and safety, however, ongoing advancements are making it possible to overcome these hurdles. As research progresses, LNPs will likely play a crucial role in the future of gene therapy.
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